Reserpine Causes Neuroendocrine Toxicity, Inducing Impairments in Cognition via Disturbing Hypothalamic–Pituitary–Thyroid Axis in Zebrafish

Reserpine is used as a cheap and effective first-line antihypertensive, and presently, it is applied as treatment for difficult-to-control cases of hypertension. Despite its significance, reserpine's neuroendocrine toxicity remains largely underexplored. Here, we investigated the effects of reserpine on development, locomotion, central nervous system (CNS) neurons, thyroid development, and the expression of genes related to neurodevelopment, endocrine, learning and memory, and depression in zebrafish exposed to different doses of reserpine ranging from 0.5 mg/L to 16 mg/L. The results of our study demonstrated that reserpine exerts dose-dependent toxicity on the neuroendocrine system (NES). An investigation into its underlying mechanism suggests that reserpine disrupted the hypothalamic-pituitary-thyroid (HPT) axis via down-regulating <i>hhex</i>, <i>tg</i>, and <i>tshβ</i> genes, impairing thyroid hormone synthesis and endocrine balance. Meanwhile, it affected neurodevelopment, as evidenced by the reduced expression of <i>gfap</i>, <i>gap43</i>, <i>mbp</i>, <i>syn2a</i>, and <i>tuba1b</i> genes, which compromised neuronal structure and function, while impaired neurotransmitter release and uptake could occur due to the suppression of <i>crhb</i> and <i>mao</i> genes. To conclude, these findings illustrate the interconnected impact of pathways involved in endocrine and neurodevelopment in reserpine-induced toxicity.